U.S. patent number 8,507,560 [Application Number 13/300,729] was granted by the patent office on 2013-08-13 for pharmaceutical compositions comprising 3,4-dihydroisoquinolin-2(1h)-yl-3-phenylurea derivatives having formyl peptide receptor like-1 (fprl-1) agonist or antagonist activity.
This patent grant is currently assigned to Allergan, Inc.. The grantee listed for this patent is Richard L. Beard, John E. Donello, Michael E. Garst, Veena Viswanath. Invention is credited to Richard L. Beard, John E. Donello, Michael E. Garst, Veena Viswanath.
United States Patent |
8,507,560 |
Beard , et al. |
August 13, 2013 |
**Please see images for:
( Certificate of Correction ) ** |
Pharmaceutical compositions comprising
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivatives having
formyl peptide receptor like-1 (FPRL-1) agonist or antagonist
activity
Abstract
The present invention relates to a method of treating a disorder
associated with modulation of the FPRL-1 receptor which comprises
administering a therapeutically effective amount of a
pharmaceutical composition comprising a
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivative.
Inventors: |
Beard; Richard L. (Newport
Beach, CA), Donello; John E. (Dana Point, CA), Garst;
Michael E. (Newport Beach, CA), Viswanath; Veena
(Irvine, CA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Beard; Richard L.
Donello; John E.
Garst; Michael E.
Viswanath; Veena |
Newport Beach
Dana Point
Newport Beach
Irvine |
CA
CA
CA
CA |
US
US
US
US |
|
|
Assignee: |
Allergan, Inc. (Irvine,
CA)
|
Family
ID: |
45316059 |
Appl.
No.: |
13/300,729 |
Filed: |
November 21, 2011 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20120142726 A1 |
Jun 7, 2012 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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61419381 |
Dec 3, 2010 |
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Current U.S.
Class: |
514/596; 546/141;
564/53; 514/309; 564/47; 564/49 |
Current CPC
Class: |
A61K
31/472 (20130101); A61P 11/06 (20180101); A61P
11/00 (20180101); A61P 35/00 (20180101); A61P
25/28 (20180101); A61P 17/02 (20180101); A61P
29/00 (20180101); A61K 31/4725 (20130101); A61P
27/06 (20180101); A61P 1/02 (20180101); A61P
17/06 (20180101); A61P 17/08 (20180101); A61P
17/14 (20180101); A61P 19/02 (20180101); A61P
27/14 (20180101); A61P 9/10 (20180101); A61P
17/10 (20180101); A61P 27/02 (20180101); A61P
9/00 (20180101); A61P 33/02 (20180101) |
Current International
Class: |
A01N
47/28 (20060101); A61K 31/17 (20060101); A61K
31/47 (20060101); A01N 43/42 (20060101); C07D
217/02 (20060101); C07C 273/00 (20060101); C07C
275/00 (20060101) |
Field of
Search: |
;514/596,309 ;546/141
;564/47,49,53 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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03-082314 |
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Oct 2003 |
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WO |
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2005-047899 |
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May 2005 |
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WO |
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2005-056528 |
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Jun 2005 |
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WO |
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Other References
Mar. 24, 2010, RN-1214189-38-4, Chemical Abstracts Service,
Columbus, Ohio. cited by applicant .
Apr. 13, 2001, RN-331238-30-3, Chemical Abstracts Service,
Columbus, Ohio. cited by applicant .
Apr. 13, 2001, RN-331252-08-5, Chemical Abstracts Service,
Columbus, Ohio. cited by applicant .
May 8, 2001, RN-334923-53-4, Chemical Abstracts Service, Columbus,
Ohio. cited by applicant .
Aug. 11, 2008, RN-1040195-78-5, Chemical Abstracts Service,
Columbus, Ohio. cited by applicant .
1980, Remington's Pharmaceutical Sciences, 16th Edition, Mack
Publishing Company, Easton, Pa. cited by applicant .
Abdul Rasheed et al, 2008, Concise and Efficient Synthesis of
Highly Potent and Selective Dipeptidyl Peptidase II Inhibitors,
Synthetic Communications, 38, 162-169. cited by applicant .
Charles Serhan et al, 2011, Resolvins and Protectins in
Inflammation Resolution, American Chemical Society, 111,5922-5943.
cited by applicant .
Driss El Kebir et al, Sep. 1, 2008, Opposing Regulation of
Neutrophil Apoptosis Through the Formyl Peptide Receptor-Like
1/Lipoxin A4 Receptor: Implications for Resolution of Inflammation,
Journal of Leukocyte Biology, 84 (3), 600-606. cited by applicant
.
Heinrich Stahl, 2002, Handbook of Pharmaceutical Salts, 329-345,
Verlag Helvetica Chemica Acta--Zurich. cited by applicant .
Mauro Perretti et al, 2010, Therapeutic Anti-Inflammatory
Protential of Formyl-Peptide Receptor Agonists, Pharmacology &
Research, 127, 175-188. cited by applicant .
Youhong Cui et al, Oct. 1, 2002, Potential Role of the Formyl
Peptide Receptor-Like 1 (FPRL1) in Inflammatory Aspects of
Alzheimer's Disease, Journal of Leukocyte Biology, 72 (4), 628-635.
cited by applicant .
Patent Cooperation Treaty, Notification of Transmittal of the
International Search Report and the Written Opinion of the
International Searching Authority, or the Declaration, Form
PCT/ISA/220, Int. App. No. PCT/US2011/061348, Mar. 16, 2012. cited
by applicant.
|
Primary Examiner: Carter; Kendra D
Attorney, Agent or Firm: Ene; Doina G.
Parent Case Text
RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application
Ser. No. 61/419,381, filed Dec. 3, 2010, the disclosure of which is
hereby incorporated in its entirety herein by reference
Claims
What is claimed is:
1. A method of modulating the N-formyl peptide receptor like-1
(FPRL-1) receptor comprising administering to a mammal in need
thereof, a pharmaceutical composition comprising a therapeutically
effective amount of at least one compound selected from:
##STR00009##
2. A pharmaceutical composition comprising as active ingredient a
therapeutically effective amount of at least one compound according
to claim 1 and a pharmaceutically acceptable adjuvant, diluent or
carrier.
3. A pharmaceutical composition according to claim 2 wherein the
compound is: ##STR00010##
4. A pharmaceutical composition according to claim 2 wherein the
compound is: ##STR00011##
5. A pharmaceutical composition according to claim 2 wherein the
compound is: ##STR00012##
6. A pharmaceutical composition according to claim 2 wherein the
compound is: ##STR00013##
7. The method of claim 1 wherein the mammal is a human.
Description
FIELD OF THE INVENTION
The present invention relates generally to pharmaceutical
compositions of certain
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivatives and their
use as modulators of the formyl peptide receptor. The invention
relates specifically to the use of certain well-defined compounds
having formyl peptide receptor like-1 (FPRL-1) agonist or
antagonist activity.
BACKGROUND OF THE INVENTION
FPRL-1 (N-formyl peptide receptor like-1) is a G protein-coupled
receptor that is expressed on inflammatory cells such as monocytes
and neutrophils, as well as T cells and has been shown to play a
critical role in leukocyte trafficking during inflammation and
human pathology. FPRL-1 is an exceptionally promiscuous receptor
that responds to a large array of exogenous and endogenous ligands,
including Serum amyloid A (SAA), chemokine variant sCK.beta.8-1,
the neuroprotective peptide humanin, anti-inflammatory eicosanoid
lipoxin A4 (LXA4) and glucocotricoid-modulated protein annexin A1.
FPRL-1 transduces anti-inflammatory effects of LXA4 in many
systems, but it also can mediate the pro-inflammatory signaling
cascade of peptides such as SAA. The ability of the receptor to
mediate two opposite effects is proposed to be a result of
different receptor domains used by different agonists.
Activation of FPRL-1 by lipoxin A4 or its analogs and by Annexin I
protein has been shown to result in anti-inflammatory activity by
promoting active resolution of inflammation which involves
inhibition of polymorphonuclear neutrophils (PMNs) and eosinophils
migration and also stimulate monocyte migration enabling clearance
of apoptotic cells from the site of inflammation in a nonphlogistic
manner. In addition, FPRL1 has been shown to inhibit NK
cytotoxicity and promote activation of T cells which further
contributes to down regulation of tissue damaging inflammatory
signals. FPRL-1/LXA4 interaction has been shown to be beneficial in
experimental models of ischemia reperfusion, angiogenesis, dermal
inflammation, chemotherapy-induced alopecia, ocular inflammation
such as endotoxin-induced uveitis, corneal wound healing,
re-epithelialization etc. FPRL-1 thus represents an important novel
pro-resolutionary molecular target for the development of new
therapeutic agents in diseases with excessive inflammatory
responses.
SUMMARY OF THE INVENTION
It has now been discovered the use of a group of
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea compounds as potent
and selective FPRL-1 modulators. The present invention relates to a
method of treating a disorder or a condition associated with
modulation of the FPRL-1 receptor which comprises administering a
therapeutically effective amount of a composition comprising a
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivatives. The
compounds in accordance with the present invention are thus of use
in medicine, for example in the treatment of humans with diseases
and conditions that are alleviated by FPRL-1 modulation. The term
"modulator" as used herein, includes but is not limited to:
receptor agonist, antagonist, inverse agonist, inverse antagonist,
partial agonist, partial antagonist.
In one aspect, the invention provides a pharmaceutically
composition comprising a therapeutically effective amount of a
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivative selected
from the group of compounds from Table 1:
TABLE-US-00001 Num- ber Structure Com- pound 1 ##STR00001## Com-
pound 2 ##STR00002## Com- pound 3 ##STR00003## Com- pound 4
##STR00004##
The compounds from Table 1 are available from commercial sources
such as Aurora Fine Chemicals LLC.
The term "pharmaceutically acceptable salts" refers to salts or
complexes that retain the desired biological activity of the above
identified compounds and exhibit minimal or no undesired
toxicological effects. The "pharmaceutically acceptable salts"
according to the invention include therapeutically active,
non-toxic base or acid salt forms, which the compounds of Formula I
are able to form.
The acid addition salt form of the compounds of the invention which
occur in their free form as a base can be obtained by treating the
free base with an appropriate acid such as an inorganic acid, for
example, hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, nitric acid and the like; or an organic acid such
as for example, acetic acid, hydroxyacetic acid, propanoic acid,
lactic acid, pyruvic acid, malonic acid, fumaric acid, maleic acid,
oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic
acid, benzoic acid, tannic acid, pamoic acid, citric acid,
methylsulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
formic and the like (Handbook of Pharmaceutical Salts, P. Heinrich
Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica
Acta-Zurich, 2002, 329-345).
The base addition salt form of a compound of Formula I that occurs
in its acid form can be obtained by treating the acid with an
appropriate base such as an inorganic base, for example, sodium
hydroxide, magnesium hydroxide, potassium hydroxide, Calcium
hydroxide, ammonia and the like; or an organic base such as for
example, L-Arginine, ethanolamine, betaine, benzathine, morpholine
and the like. (Handbook of Pharmaceutical Salts, P. Heinrich
Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica
Acta-Zurich, 2002, 329-345).
Compounds of the invention and their salts can be in the form of a
solvate, which is included within the scope of the present
invention. Such solvates include for example hydrates, alcoholates
and the like.
With respect to the present invention reference to a compound or
compounds, is intended to encompass that compound in each of its
possible isomeric forms and mixtures thereof unless the particular
isomeric form is referred to specifically.
Compounds according to the present invention may exist in different
polymorphic forms. Although not explicitly indicated in the above
formula, such forms are intended to be included within the scope of
the present invention.
The compounds of the invention are indicated for use in treating or
preventing conditions in which there is likely to be a component
involving the N-formyl peptide receptor like-1 receptor.
In another embodiment, there are provided pharmaceutical
compositions including at least one compound of the invention in a
pharmaceutically acceptable carrier.
In a further embodiment of the invention, there are provided
methods for treating disorders associated with modulation of the
N-formyl peptide receptor like-1 receptor.
Such methods can be performed, for example, by administering to a
subject in need thereof a pharmaceutical composition containing a
therapeutically effective amount of at least one compound of the
invention.
Therapeutic utilities of the N-formyl peptide receptor like-1
receptor modulators are ocular inflammatory diseases including, but
not limited to, wet and dry age-related macular degeneration
(ARMD), uveitis, dry eye, Keratitis, allergic eye disease and
conditions affecting the posterior part of the eye, such as
maculopathies and retinal degeneration including non-exudative age
related macular degeneration, exudative age related macular
degeneration, choroidal neovascularization, diabetic retinopathy
(proliferative), retinopathy of prematurity (ROP), acute macular
neuroretinopathy, central serous chorioretinopathy, cystoid macular
edema, and diabetic macular edema; infectious keratitis, uveitis,
herpetic keratitis, corneal angiogenesis, lymphangiogenesis,
retinitis, and choroiditis such as acute multifocal placoid pigment
epitheliopathy, Behcet's disease, birdshot retinochoroidopathy,
infectious (syphilis, lyme, tuberculosis, toxoplasmosis),
intermediate uveitis (pars planitis), multifocal choroiditis,
multiple evanescent white dot syndrome (mewds), ocular sarcoidosis,
posterior scleritis, serpiginous choroiditis, subretinal fibrosis
and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome; vasuclar
diseases/exudative diseases such as retinal arterial occlusive
disease, central retinal vein occlusion, cystoids macular edema,
disseminated intravascular coagulopathy, branch retinal vein
occlusion, hypertensive fundus changes, ocular ischemic syndrome,
retinal arterial microaneurysms, Coat's disease, parafoveal
telangiectasis, hemi-retinal vein occlusion, papillophlebitis,
central retinal artery occlusion, branch retinal artery occlusion,
carotid artery disease (CAD), frosted branch angiitis, sickle cell
retinopathy and other hemoglobinopathies, angioid streaks, familial
exudative vitreoretinopathy, and Eales disease; traumatic/surgical
conditions such as sympathetic ophthalmia, uveitic retinal disease,
retinal detachment, trauma, conditions caused by laser, conditions
caused by photodynamic therapy, photocoagulation, hypoperfusion
during surgery, radiation retinopathy, and bone marrow transplant
retinopathy; proliferative disorders such as proliferative vitreal
retinopathy and epiretinal membranes, and proliferative diabetic
retinopathy; infectious disorders such as ocular histoplasmosis,
ocular toxocariasis, presumed ocular histoplasmosis syndrome
(PONS), endophthalmitis, toxoplasmosis, retinal diseases associated
with HIV infection, choroidal disease associate with HIV infection,
uveitic disease associate with HIV infection, viral retinitis,
acute retinal necrosis, progressive outer retinal necrosis, fungal
retinal diseases, ocular syphilis, ocular tuberculosis, diffuse
unilateral subacute neuroretinitis, and myiasis; genetic disorders
such as retinitis pigmentosa, systemic disorders with accosiated
retinal dystrophies, congenital stationary night blindness, cone
dystrophies, Stargardt's disease and fundus flavimaculatus, Best's
disease, pattern dystrophy of the retinal pigmented epithelium,
X-linked retinoschisis, Sorsby's fundus dystrophy, benign
concentric maculopathy, Bietti's crystalline dystrophy, and
pseudoxanthoma elasticum; retinal tears/holes such as retinal
detachment, macular hole, and giant retinal tear; tumors such as
retinal disease associated with tumors, congenital hypertrophy of
the retinal pigmented epithelium, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, and intraocular lymphoid tumors; and
miscellaneous other diseases affecting the posterior part of the
eye such as punctate inner choroidopathy, acute posterior
multifocal placoid pigment epitheliopathy, myopic retinal
degeneration, and acute retinal pigement epitheliitis, systemic
inflammatory diseases such as stroke, coronary artery disease,
obstructive airway diseases, HIV-mediated retroviral infections,
cardiovascular disorders including coronary artery disease,
neuroinflammation, neurological disorders, pain and immunological
disorders, asthma, allergic disorders, inflammation, systemic lupus
erythematosus, psoriasis, CNS disorders such as Alzheimer's
disease, arthritis, sepsis, inflammatory bowel disease, cachexia,
asthma, atherosclerosis, human colon cancer, periodontitis, angina
pectoris, post-surgical corneal inflammation, blepharitis, MGD,
dermal wound healing, burns, skin-related diseases, including,
arsenic keratoses, inflammatory and non-inflammatory acne,
ichthyoses and other keratinization and hyperproliferative
disorders of the skin, eczema, Darriers disease, lichen planus,
prevention and reversal of glucocorticoid damage (steroid atrophy),
rosacea, atopic dermatitis, acne, telangiectasia, discreet
erythemas, erythema multiforme minor, erythema multiforme major
seborrheic dermatitis, actinic keratoses, viral warts, photoaging
rheumatoid arthritis and related inflammatory disorders, alopecia,
glaucoma, branch vein occlusion, Best's vitelliform macular
degenartion, retinitis pigmentosa, proliferative vitreoretinopathy
(PVR), and any other degenerative disease of either the
photoreceptors or the RPE (Perretti, Mauro et al. Pharmacology
& Therapeutics 127 (2010) 175-188 and Charles N. Serhan et al.
in "Resolvins and Protectins in Inflammation Resolution" Chem. Rev.
2011, 111, 5922-5943).
These compounds are useful for the treatment of mammals, including
humans, with a range of conditions and diseases that are alleviated
by the N-formyl peptide receptor like-1 receptor modulation:
including, but not limited to the treatment of wet and dry
age-related macular degeneration (ARMD), diabetic retinopathy
(proliferative), retinopathy of prematurity (ROP), diabetic macular
edema, uveitis, retinal vein occlusion, cystoids macular edema,
glaucoma, branch vein occlusion, Best's vitelliform macular
degenartion, retinitis pigmentosa, proliferative vitreoretinopathy
(PVR), and any other degenerative disease of either the
photoreceptors or the RPE.
In still another embodiment of the invention, there are provided
methods for treating disorders associated with modulation of the
FPRL-1 receptor. Such methods can be performed, for example, by
administering to a subject in need thereof a therapeutically
effective amount of at least one compound of the invention, or any
combination thereof, or pharmaceutically acceptable salts,
hydrates, solvates, crystal forms and individual isomers,
enantiomers, and diastereomers thereof.
The present invention concerns the use of a
3,4-dihydroisoquinolin-2(1H)-yl-3-phenylurea derivative of Table 1
or a pharmaceutically acceptable salt thereof, for the manufacture
of a medicament for the treatment of Therapeutic utilities of the
N-formyl peptide receptor like-1 receptor modulators are ocular
inflammatory diseases including, but not limited to, wet and dry
age-related macular degeneration (ARMD), uveitis, dry eye,
Keratitis, allergic eye disease and conditions affecting the
posterior part of the eye, such as maculopathies and retinal
degeneration including non-exudative age related macular
degeneration, exudative age related macular degeneration, choroidal
neovascularization, diabetic retinopathy (proliferative),
retinopathy of prematurity (ROP), acute macular neuroretinopathy,
central serous chorioretinopathy, cystoid macular edema, and
diabetic macular edema; infectious keratitis, uveitis, herpetic
keratitis, corneal angiogenesis, lymphangiogenesis, uveitis,
retinitis, and choroiditis such as acute multifocal placoid pigment
epitheliopathy, Behcet's disease, birdshot retinochoroidopathy,
infectious (syphilis, lyme, tuberculosis, toxoplasmosis),
intermediate uveitis (pars planitis), multifocal choroiditis,
multiple evanescent white dot syndrome (mewds), ocular sarcoidosis,
posterior scleritis, serpiginous choroiditis, subretinal fibrosis
and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome; vasuclar
diseases/exudative diseases such as retinal arterial occlusive
disease, central retinal vein occlusion, cystoids macular edema,
disseminated intravascular coagulopathy, branch retinal vein
occlusion, hypertensive fundus changes, ocular ischemic syndrome,
retinal arterial microaneurysms, Coat's disease, parafoveal
telangiectasis, hemi-retinal vein occlusion, papillophlebitis,
central retinal artery occlusion, branch retinal artery occlusion,
carotid artery disease (CAD), frosted branch angiitis, sickle cell
retinopathy and other hemoglobinopathies, angioid streaks, familial
exudative vitreoretinopathy, and Eales disease; traumatic/surgical
conditions such as sympathetic ophthalmia, uveitic retinal disease,
retinal detachment, trauma, conditions caused by laser, conditions
caused by photodynamic therapy, photocoagulation, hypoperfusion
during surgery, radiation retinopathy, and bone marrow transplant
retinopathy; proliferative disorders such as proliferative vitreal
retinopathy and epiretinal membranes, and proliferative diabetic
retinopathy; infectious disorders such as ocular histoplasmosis,
ocular toxocariasis, presumed ocular histoplasmosis syndrome
(PONS), endophthalmitis, toxoplasmosis, retinal diseases associated
with HIV infection, choroidal disease associate with HIV infection,
uveitic disease associate with HIV infection, viral retinitis,
acute retinal necrosis, progressive outer retinal necrosis, fungal
retinal diseases, ocular syphilis, ocular tuberculosis, diffuse
unilateral subacute neuroretinitis, and myiasis; genetic disorders
such as retinitis pigmentosa, systemic disorders with accosiated
retinal dystrophies, congenital stationary night blindness, cone
dystrophies, Stargardt's disease and fundus flavimaculatus, Best's
disease, pattern dystrophy of the retinal pigmented epithelium,
X-linked retinoschisis, Sorsby's fundus dystrophy, benign
concentric maculopathy, Bietti's crystalline dystrophy, and
pseudoxanthoma elasticum; retinal tears/holes such as retinal
detachment, macular hole, and giant retinal tear; tumors such as
retinal disease associated with tumors, congenital hypertrophy of
the retinal pigmented epithelium, posterior uveal melanoma,
choroidal hemangioma, choroidal osteoma, choroidal metastasis,
combined hamartoma of the retina and retinal pigmented epithelium,
retinoblastoma, vasoproliferative tumors of the ocular fundus,
retinal astrocytoma, and intraocular lymphoid tumors; and
miscellaneous other diseases affecting the posterior part of the
eye such as punctate inner choroidopathy, acute posterior
multifocal placoid pigment epitheliopathy, myopic retinal
degeneration, and acute retinal pigement epitheliitis, systemic
inflammatory diseases such as stroke, coronary artery disease,
obstructive airway diseases, HIV-mediated retroviral infections,
cardiovascular disorders including coronary artery disease,
neuroinflammation, neurological disorders, pain and immunological
disorders, asthma, allergic disorders, inflammation, systemic lupus
erythematosus, psoriasis, CNS disorders such as Alzheimer's
disease, arthritis, sepsis, inflammatory bowel disease, cachexia,
angina pectoris, post-surgical corneal inflammation, blepharitis,
MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne,
psoriasis, telangiectasia, discreet erythemas, erythema multiforme
minor, erythema multiforme major seborrheic dermatitis, actinic
keratoses, viral warts, photoaging, rheumatoid arthritis and
related inflammatory disorders, alopecia, glaucoma, branch vein
occlusion, Best's vitelliform macular degenartion, retinitis
pigmentosa, proliferative vitreoretinopathy (PVR), and any other
degenerative disease of either the photoreceptors or the RPE
(Perretti, Mauro et al. Pharmacology & Therapeutics 127 (2010)
175-188.)
The actual amount of the compound to be administered in any given
case will be determined by a physician taking into account the
relevant circumstances, such as the severity of the condition, the
age and weight of the patient, the patient's general physical
condition, the cause of the condition, and the route of
administration.
The patient will be administered the compound orally in any
acceptable form, such as a tablet, liquid, capsule, powder and the
like, or other routes may be desirable or necessary, particularly
if the patient suffers from nausea. Such other routes may include,
without exception, transdermal, parenteral, subcutaneous,
intranasal, via an implant stent, intrathecal, intravitreal,
topical to the eye, back to the eye, intramuscular, intravenous,
and intrarectal modes of delivery. Additionally, the formulations
may be designed to delay release of the active compound over a
given period of time, or to carefully control the amount of drug
released at a given time during the course of therapy.
In another embodiment of the invention, there are provided
pharmaceutical compositions including at least one compound of the
invention in a pharmaceutically acceptable carrier thereof. The
phrase "pharmaceutically acceptable" means the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
Pharmaceutical compositions of the present invention can be used in
the form of a solid, a solution, an emulsion, a dispersion, a
patch, a micelle, a liposome, and the like, wherein the resulting
composition contains one or more compounds of the present
invention, as an active ingredient, in admixture with an organic or
inorganic carrier or excipient suitable for enteral or parenteral
applications. Invention compounds may be combined, for example,
with the usual non-toxic, pharmaceutically acceptable carriers for
tablets, pellets, capsules, suppositories, solutions, emulsions,
suspensions, and any other form suitable for use. The carriers
which can be used include glucose, lactose, gum acacia, gelatin,
mannitol, starch paste, magnesium trisilicate, talc, corn starch,
keratin, colloidal silica, potato starch, urea, medium chain length
triglycerides, dextrans, and other carriers suitable for use in
manufacturing preparations, in solid, semisolid, or liquid form. In
addition auxiliary, stabilizing, thickening and coloring agents and
perfumes may be used. Invention compounds are included in the
pharmaceutical composition in an amount sufficient to produce the
desired effect upon the process or disease condition.
Pharmaceutical compositions containing invention compounds may be
in a form suitable for oral use, for example, as tablets, troches,
lozenges, aqueous or oily suspensions, dispersible powders or
granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any
method known in the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of a sweetening agent such as
sucrose, lactose, or saccharin, flavoring agents such as
peppermint, oil of wintergreen or cherry, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets containing invention compounds in
admixture with non-toxic pharmaceutically acceptable excipients may
also be manufactured by known methods. The excipients used may be,
for example, (1) inert diluents such as calcium carbonate, lactose,
calcium phosphate or sodium phosphate; (2) granulating and
disintegrating agents such as corn starch, potato starch or alginic
acid; (3) binding agents such as gum tragacanth, corn starch,
gelatin or acacia, and (4) lubricating agents such as magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be employed.
In some cases, formulations for oral use may be in the form of hard
gelatin capsules wherein the invention compounds are mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin. They may also be in the form of soft gelatin
capsules wherein the invention compounds are mixed with water or an
oil medium, for example, peanut oil, liquid paraffin or olive
oil.
The pharmaceutical compositions may be in the form of a sterile
injectable suspension. This suspension may be formulated according
to known methods using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Sterile, fixed oils are conventionally
employed as a solvent or suspending medium. For this purpose any
bland fixed oil may be employed including synthetic mono- or
diglycerides, fatty acids (including oleic acid), naturally
occurring vegetable oils like sesame oil, coconut oil, peanut oil,
cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate
or the like. Buffers, preservatives, antioxidants, and the like can
be incorporated as required.
The pharmaceutical compositions of the invention may also be
administered in the form of suppositories for rectal administration
of the drug. These compositions may be prepared by mixing the
invention compounds with a suitable non-irritating excipient, such
as cocoa butter, synthetic glyceride esters of polyethylene
glycols, which are solid at ordinary temperatures, but liquefy
and/or dissolve in the rectal cavity to release the drug.
Since individual subjects may present a wide variation in severity
of symptoms and each drug has its unique therapeutic
characteristics, the precise mode of administration and dosage
employed for each subject is left to the discretion of the
practitioner.
The pharmaceutical compositions described herein are useful as
medicaments in mammals, including humans, for treatment of diseases
and/or alleviations of conditions which are responsive to treatment
by agonists or functional antagonists of the N-formyl peptide
receptor like-1 (FPRL-1) receptor. Thus, in further embodiments of
the invention, there are provided methods for treating a disorder
associated with modulation of the N-formyl peptide receptor like-1
(FPRL-1) receptor. Such methods can be performed, for example, by
administering to a subject in need thereof a pharmaceutical
composition containing a therapeutically effective amount of at
least one invention compound. As used herein, the term
"therapeutically effective amount" means the amount of the
pharmaceutical composition that will elicit the biological or
medical response of a subject in need thereof that is being sought
by the researcher, veterinarian, medical doctor or other clinician.
In some embodiments, the subject in need thereof is a mammal. In
some embodiments, the mammal is human.
Biological Data
Biological activity of compounds according to Table1 is set forth
in Table 2 below. CHO-Ga16 cells stably expressing FPRL1 were
cultured in (F12, 10% FBS, 1% PSA, 400 .mu.g/ml geneticin and 50
.mu.g/ml hygromycin) and HEK-Gqi5 cells stable expressing FPR1 were
cultured in (DMEM high glucose, 10% FBS, 1% PSA, 400 .mu.g/ml
geneticin and 50 .mu.g/ml hygromycin). In general, the day before
the experiment, 18,000 cells/well were plated in a 384-well clear
bottom poly-d-lysine coated plate. The following day the screening
compound-induced calcium activity was assayed on the
FLIPR.sup.Tetra. The drug plates were prepared in 384-well
microplates using the EP3 and the MultiPROBE robotic liquid
handling systems. Compounds were tested at concentrations ranging
from 0.61 to 10,000 nM. Results are expressed as EC.sub.50 (nM) and
efficacy values.
TABLE-US-00002 TABLE 2 FPRL-1 Ga16-CHO EC.sub.50 Number Structure
(eff) Compound 1 ##STR00005## 143 nM (0.61) Compound 2 ##STR00006##
91 nM (0.79) Compound 3 ##STR00007## 32 nM (0.76) Compound 4
##STR00008## 59 nM (0.71)
* * * * *